Tetrahydropyridine derivatives

ABSTRACT

Tetrahydropyridine derivatives and processes for the preparation thereof are disclosed. These tetrahydropyridine compounds are useful as psychosedative agents.

United States Patent 1 1 Edenhoier 1 TETRAHYDROPYRIDINE DERIVATIVES [75]Inventor: Albrecht EdenhofenRiehen.

Switzerland [73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: May 21, 1973 [21] Appl. No.: 362,636

Related US. Application Data [62] Division of Ser. No. 148,119. May 28.1971. Pat. No.

[30] Foreign Application Priority Data June 19. 1970 Switzerland 9318/7052 us. Cl ..260/294.8 F; 260/294.8 0;

260/295 AM; 260/296 R; 260/297 R;

[51] Int. Cl. C07d 31/48; C07d 31/50 [58] FieldofSearch..260/294.8F,294.8G,

260/295 AM, 296 R, 297 R [451 Apr. 22, 1975 OTHER PUBLICATIONS Robertset 211.. Basic Principles of Organic Chemistry.

Pages 384. 386, 421, 750. 751. (Benjamin Publishers. 1965), OD 251 RS8C6.

Primary E.\'aminerAlan L. Rotman Attorney, Agent, or Firm-Samuel L.Welt; Bernard S. Leon; Frank P. Hoffman [57 ABSTRACT T etrahydropyridinederivatives and processes for the preparation thereof are disclosed.These tetrahydropyridine compounds are useful as psychosedative agents.

1 Claim, No Drawings TETRAHYDROPYRIDINE DERIVATIVES This is division, ofapplication Scr. No. M8,] l9 filed May 28, 1971, now US. Pat. No.3,758,483.

DESCRIPTION OF THE INVENTION La ch-NM R; Q

l i I R2 wherein R signifies hydrogen, lower alkyl, lower alkanoyl,lower alkylsulfonyl, cycloalkyl or cycloalkyllower alkyl;

R signifies hydrogen, lower alkyl, cycloalkyl or cycloalkyllower alkyl;

R signifies fluorine, chlorine or lower alkoxy;

X signifies an oxygen atom or a sulfur atom and the pharmaceuticallyacceptable acid addition salts thereof.

As used herein, either alone or in combination such as in loweralkyl-sulfonyl, the term lower alkyl" comprchcnds straight or branchedchain hydrocarbon groups having from 1 to 7 carbon atoms, preferablyfrom I to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl,n-hexyl and the like. The term lower alkoxy" designates straight orbranched chain saturated hydrocarbonxoy groups containing from 1 to 7carbon atoms, preferably from 1 to 4 carbon atoms, such as methoxy,ethoxy, propoxy and the like. The term "lower alkanoyl" denotes theresidue of a straight or branched chain aliphatic carboxylic acid,containing from 1 to 7 carbon atoms, for example formyl, acetyl,propionyl, isobutyryl and n-valeryl. The term cycloalkyl" encompassescyclic hydrocarbon groups having from 3 to 6 carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl and the like. Examples of thecycloalkyl-lower alkyl groups include cyclopropyl-methyl,cyclopropyl-ethyl and the like.

A preferred class of compounds falling within the scope of formula I arethose wherein X represents an oxygen atom, i.e. compounds of the formulaR3 Ia wherein R,-R are as described above.

Another preferred class of compounds falling within the scope of formulaI are those wherein R signifies fluorine, i.e. compounds of the formulaI x-cHz-cHzlnNw F 1 wherein R R and x are as described above.

Particularly preferred of the compounds of formula 1 above are thosewherein R represents a lower alkanoyl group, preferably the acetylgroup, R represents hydrogen, R represents fluorine and X representsoxygen. Most preferred of the compounds of formula I is: 42[4-(p-fluorophenyl)-3,6-dihydro-l 2H )-pyridyl]- ethoxy}-acetanilide.

The novel compounds of formula I can be prepared following a variety ofsynthetic routes.

A. In one such process aspect, the compounds of formula l above can beprepared by condensing a compound of the general formula wherein R is asdescribed above.

Suitable leaving groups in the starting materials of formula II aboveinclude a halogen atom, preferably chlorine or bromine, a loweralkylsulfonyloxy group, preferably mesyloxy, an arylsulfonyloxy group,preferably tosyloxy or benzene-sulfonyloxy, or the group N(R A-in whichR signifies lower alkyl and A signifies the anion of an acid.

The condensation of a compound of formula II with a compound of formulalll is expediently effected in the presence of a polar organic solvent.Suitable for this purpose are lower alkanols such as methanol, ethanol,isopropanol and the like; cyclic ethers such as tetrahydrofuran anddroxane; and dimethylformamide or dimethyl sulfoxide. The condensationis advantageously effected at a temperature between room temperature andthe reflux temperature of the reaction mixture. Where, in the startingmaterial of formula II the leaving group designated as Z represents ahalogen atom or a lower alkyl or aryl-sulfonyloxy group, thecondensation reaction is preferably carried out in the presence of anacid binding agent, for example in the presence of an alkali carbonatesuch as potassium carbonate.

The starting materials of formula II above may be prepared by reacting acompound of the formula wherein R R and X are as described above with aZ-halo-ethanol of the formula haloCH CH OH v to yield a compound of theformula X-CH2CH OH VI R -lll wherein R R and X are as described above.

The compound of formula VI so obtained can then be reacted with ahalogenating agent, such as thionyl chloride to obtain the compound offormula II wherein Z signifies halogen. This halogenation reaction ispreferably effected in the presence of an inert organic solvent such aschloroform or benzene at a temperature between about room temperatureand the reflux temperature of the reaction mixture.

Alternately, the compound of formula VI above can be reacted with analkylor aryl-substituted sulfonic acid halide, preferably the chloride,to yield the desired compound of formula II wherein Z signifies analkylor arylsulfonyloxy group. This reaction is expediently effected inthe presence of an acid binding agent at a temperature between about Cand room temperature.

The compounds of formula II above wherein Z represents the group -N(R A,R and A being as defined above, can be prepared by amination of thecorresponding compounds of formula II wherein Z signifies halogen. Thisamination can be effected by reacting the halo-substituted compound offormula II with a dialkylamine, preferably dimethylamine; this reactionis expediently effected in a closed vessel at an elevated temperature,for example between about 50 and 150C. The product obtained as a resultof this amination is subsequently quaternized by reaction with analkylating agent such as an alkylchloride, alkyl bromide or alkylsulfate, preferably methyl chloride, methyl bromide or dimethyl sulfate.The quaternization is preferably carried out at a temperature of fromabout room temperature to about 75C. Both the amination andquaternization are expediently carried out in the presence of an inertsolvent such as an alkanol, i.e. methanol, or in dioxane or benzene.

The starting materials of formula II wherein X signifies oxygen and theleaving group Z is a halogen atom may also be prepared by reacting acompound of formula IV wherein X is oxygen with an excess of a 1,2-dihaloethane, preferably, l,2-dibromoethane in the presence of an excessof aqueous alkali, preferably caustic soda. This reaction is preferablycarried out at a temperature between room temperature and the boilingpoint of the reaction mixture.

The starting materials of formula III wherein R signifies lower alkoxycan be prepared, for example, by employing a Grignard reaction. Thus,for instance, the reaction between N-benzyl-4-piperidone andp-methoxyphenyl magnesium bromide, followed by hydrogenolytic cleavageof the benzyl group and treatment with a dehydrating agent such as, forexample, thionyl chloride or alcoholic hydrochloric acid, yields thedesired compound of formula III wherein R is methoxy.

B. In another process aspect of the present invention, the compounds offormula I above can be prepared by reacting a compound of the formula fi-N wherein R R and X are as described above and M signifies an alkalimetal or a halomagnesium radical with a compound of the formula whereinR is as described above and L is a suitable leatving group.

The substituent M in the starting materials of formula VII preferablyrepresents an alkali metal, especially sodium or potassium. In addition,M can also represent a halo-magnesium radical such as thebromo-magnesium or chloro-magnesium radical.

The leaving group in the compounds of formula VIII designated by thesymbol L is preferably a halogen atom, especially chlorine or bromine,or an alkylor aryl-sulfonyloxy group, especially mesyloxy or tosyloxy.

The reaction between a compound of formula VII wherein M is potassium analkali metal and a compound of formula VIII is effected in the presenceof an alkali alkanolate, for example sodium ethanolate, in thecorresponding alkanol, for example, ethanol. When the M substituent inthe compounds of formula VII represents a halo-magnesium radical,the-reaction of this formula VII compound with a compound of formulaVIII is preferably carried out in a polar organic solvent such as in anether, i.e. dimethyl ether, tetrahydrofuran or dioxane. This reaction ispreferably carried out at a temperature between room temperature and thereflux temperature of the reaction mixture.

The starting materials of formula VIII are expediently prepared byreacting a compound of formula III above with a Z-halo-ethanol,preferably 2-ch1oro-ethanol, to

yield a compound of the formula amalgam-NM a IX wherein R is asdescribed above.

This reaction is preferably effected in polar solvent such as, forexample, an alkanol, i.e. methanol, ethanol and the like,dimethylformamide or dimethyl sulfoxide. It is preferable to carry outthis reaction in the presence of an acid binding agent, for example, inthe presence of an alkali carbonate such as potassium carbonate and at atemperature between room temperature and the reflux temperature of thereaction medium.

The compound of formula IX thus obtained can subsequently be reactedwith a halogenating agent such as 30 thienyl chloride to yield thedesired starting material of formula Vlll in which L represents ahalogen atom. This halogenation is preferably effected in the presenceof an inert solvent, for example benzene or chloroform. at a temperaturebetween room temperature and the reflux temperature of the reactionmixture.

The compound of formula IX above can alternatively be reacted with analkylor arylsubstituted sulfonic acid halide, preferably the chloride,to give the desired starting material of formula VIII in which Lrepresents an alkylor aryl-substituted sulfonyloxy group. This re--action is expediently effected in the presence of an acid binding agent,for example, pyridine or triethylamine, at a temperature between about Cand room temperature.

C. In a further process aspect of the present invention, the desiredcompounds of formula I above canbe prepared by dehydrating a compound ofthe formula wherein R R R and X are as described above. The dehydrationof the compounds of formula X above is effected employing conventionaltechniques as for example by treating said compound with a standarddehydrating agent. Suitable dehydrating agents for this purpose includeacetic acid anhydride, acetyl chloride, thionyl chloride,p-toluene-sulfonic acid, sulfuric acid, aluminum oxide, calcium chlorideand the like. This dehydration reaction is expediently effected in aninert 10 anol and the like, dimethylformamide, dimethyl sulfoxide ortetrahydrofuran and in the presence of an acid binding agent such as analkali carbonate, preferably potassium carbonate. The temperature rangefor this reaction is preferably between room temperature and the refluxtemperature of the reaction medium.

D. In another process aspect of this invention, the desired compounds offormula I above can be prepared by treating a compound of the generalformula wherein R,, R R and X are as described above with a mineralacid.

The treatment of the starting material of formula XI with a mineral acidis preferably carried out using concentrated hydrochloric acid. In sodoing, the acid treatment of the formula XI compound is effected at atemperature between about 0C and the reflux temperature of the reactionmixture, preferably at an elevated temperature, for a prolonged period,for example between 3 to 6 hours. It should be noted that any loweralkanoyl 40 group present in the starting material of formula XI as U on.4" momma-NW3 X amide, dimethyl sulfoxide or tetrahydrofuran and in thepresence of an acid binding agent such as, for example,

an alkali carbonate, preferably potassium carbonate.

This reaction is expediently carried out at a tempera- 7 XCH2-CH2-N\ OXII wherein R and X are as described above.

The reduction of the starting material of formula XII is preferablycarried out by treatment of said compound with hydrazine in the presenceof a noble metal catalyst such as palladium on charcoal or platinumoxide. Alternatively, the reduction can also be carried out by treatmentof the formula XII compound with sodium dithionite or with nascenthydrogen which can be provided, for example, by using a mineral acidsuch as hydrochloric acid and a metal which is capable of liberatinghydrogen such as zinc or iron. This reduction is expediently conductedin the presence ofa lower alkanol, preferably ethanol, or in a cyclicether, preferably tetrahydrofuran. The reduction is preferably carriedout at a temperature between room temperature and the reflux temperatureof the reaction mixture.

The starting materials of formula XII can be prepared, for example, bycondensing a 4-nitro-l-(2-haloethoxy or Z-haIo-ethylthio)-benzene with acompound of formula III above. The conditions employed for thecondensation of the appropriately substituted benzene compound with theformula III compound are essem tially the same as those describedinprocessa s pect (A) above for the condensation of compounds offormulae II and III.

F. In another process aspect of the instant invention, a compound of thegeneral formula R25 I XIII 8 x-cu -cu -uw- R3 wherein R R and X are asdescribed above and R, signifies hydrogen, lower alkyl, lower alkanoyl,cycloalkyl or cycloalkyl-lower alkyl.

The starting material of formula XIII is reduced by treatment of saidcompound with a complex metal hydride, preferably lithium aluminumhydride. This reduction is preferably effected in an organic solventsuch as ether, tetrahydrofuran, dioxane or diglyme, and at a temperaturebetween about 0C and the reflux temperature of the reaction mixture. If,in the starting materials of formula XIII, R and R each signify anoxygen atom, the nitro group present in the starting material is firstreduced following the procedures set forth in process aspect (E) above,and then the acid amide function is reduced as described above.

The starting materials of formula XIII can, for examformula H2 CO-haloXIV wherein R R and X are as described above with a compound of formulaIII above. The halogen leaving group in the compounds of formula XIV ispreferably chlorine. This reaction is expediently effected in thepresence of an inert organic solvent such as benzene or chloroform andin the presence of an acidbinding agent, preferably a tertiary organicbase such as triethylamine or pyridine. The reaction is preferablycarried out at a temperature between 0C. and the reflux temperature ofthe reaction mixture.

G. The compounds of formula I above wherein R,

signifies lower alkyl,. lower alkanyol, lower alkylsulfonyl, cycloalkylor cycloalkyl-lower alkyl can be prepared following conventionaltechniques by introducing the desired R substituent into thecorresponding compound of the formula I wherein R signifies hydrogen,i.e., into a compound of the formula wherein R R and X are as describedabove.

The introduction of the desired R substituent into the compound offormula Id above can be affected following conventional alkylating,alkanoylating or alkylsulfonylating techniques. Thus, for example, alower alkyl, cycloalkyl or cycloalkyl-lower alkyl group can beintroduced using standard alkylating procedures as by reacting theformula ld compound with an appropriate alkylating agent such as methyliodide, cyclopropylbromide, dimethyl sulfate and the like. In a furtherexample, the compound of formula Id can be treated with an appropriateacid halide or acid anhydride such as acetyl chloride, acetic anhydride,cyclopropane carboxylic acid chloride or methane sulfonic acid chlorideto yield the correspondingly substituted compound of formula I. Thetreatment with an acid chloride is preferably effected in the presenceof an acid-binding agent, for example, a tertiary organic base such astriethylamine or pyridine, and an inert organic solvent such as benzene,chloroform, tetrahydrofuran or dimethyl sulfoxide and at a temperaturebetween room temperature and the reflux temperature of the reactionmedium. The treatment with an acid anhydride is preferably effected in apolar protonic solvent such as an alkanol, for example methanol, or inthe presence of a dilute alkanecarboxylic acid, for example, diluteacetic acid. This reaction is expediently carried out at a temperaturebetween about C. and about 50C., preferably at room temperature.

This process aspect represents a preferred procedure for the preparationof the compounds of formula I above wherein R signifies a loweralkyl-sulfonyl group. It is also the preferred procedure for introducinga lower alkylsulfonyl group, when desired, into the starting materialsof formulae 11, VII, X and XI above wherein R signifies hydrogen.

The compounds of formula 1 above wherein R, signifies a lower alkanoylgroup can be saponified following conventional techniques, as forexample, by treating said compound with dilute aqueous caustic alkali orwith aqueous acid. It is advantageous to use about percent hydrochloricacid at an elevated temperature, especially at the reflux temperature ofthe reaction mixture.

The compounds of formula I above are basic and thus form acid additionsalts with both pharmaceutically acceptable organic or inorganic acids,for example, with hydrohalic acids such as hydrochloric acid,hydrobromic acid and hydroiodic acid, with other mineral acids such assulfuric acid, phosphoric acid and nitric acid, as well as with organicacids such as tartaric acid, citric acid, oxalic acid, camphorsulfonicacid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid,ascorbic acid, maleic acid, mandelic acid and the like. Preferred saltsare the hydrohalides, especially the hydrochlorides. The acid additionsalts are preferably manufactured in a suitable solvent such as ethanolor acetonitrile by treatment of the free base with the correspondingnon-aqueous acid.

The compounds of formula I above are, in part, crystalline substanceswhich are relatively readily soluble in dimethyl sulphoxide,dimethylformamide, in chlorinated hydrocarbons such as, for example,chloroform or methylene chloride and in alkanols such as methanol orethanol, but which are relatively insoluble in water.

The acid addition salts of the compounds of formula I are crystallinesubstances. They are readily soluble in dimethyl sulphoxide,dimethylformamide, in alkanols such as methanol or ethanol and, usually,also in water. They are relatively insoluble in benzene, petroleum etherand in chlorinated hydrocarbons such as, for example, chloroform ormethylene chloride.

As indicated above, the compounds of formula I above exhibitpsychosedative activity. The psychosedative activity of thetetrahydropyridine derivatives of formula I is demonstrated in warmblooded animals using the standard open field test withrats'[Psychopharmacologia I, 389-392 (1960)]. The dosage which caused a50 percent decrease (in comparison to the untreated controls) in thenumber of diameter crossings is expressed as the ED The results of thetest for representative compounds of formula I are shown in thefollowing Table:

ethoxyI-aniline The tetrahydropyridine derivatives provided by thisinvention can be used as medicaments; for example, in the form ofpharmaceutical preparations which contain them in association with acompatible pharmaceutical carrier. This carrier can be an organic orinorganic inert carrier material which is suitable for enteral orparenteral application such as, for example, gelatin, gum arabic,lactose, starches, magnesium stearate, talc, vegetable oils,polyalkylene glycols etc. The pharmaceutical preparations are preferablymade up in solid form (e.g., as tablets, dragees, suppositories orcapsules). They can also contain yet other therapeutically valuablesubstances.

Expedient pharmaceutical dosage forms contain about 5-100 mg. of acompound of formula I. Expedient oral dosage ranges lie at about 0.1mg/kg/day to about 10 mg/kg/day. However, the stated ranges can beextended upwards or downwards depending on the individual requirement ofthe patient or the directions given by the specialist.

The starting materials of formulae X, XI, XII, and Xlll are novel and assuch form a part of the present invention. The following examplesfurther illustrate the scope of the noted invention. Unless otherwiseindicated, the temperature stated are in degrees centigrade.

EXAMPLE I 21.4 g. of 4-(p-fluorophenyl)-l,2,3,6- tetrahydropyridinehydrochloride, 25.8 g. of 4-(2- bromoethoxy)acetanilide, 30 g. ofpotassium carbonate and a few crystals of potassium iodide are heatedunder reflux conditions in 200 ml. of ethanol and 20 ml. of water for 24hours. While still hot, the mixture is decanted from the aqueous phase,ml. of water are added and the mixture is allowed to cool, with crude4-[2-[4-(p-fluorophenyl)-3,6-dihydro-l(2Hl-pyridyl- ]ethoxy}acetanilidecrystallizing out of solution. This is dissolved in a mixture of 150 ml.of methanol and 50 ml. of acetic acid ethyl ester and converted byaddition of alcoholic hydrochloric acid, until the mixture becomesacidic, into the hydrochloride, which crystallizes after the addition of100 ml. of acetic acid ethyl ester. The hydrochloride melts at 214-216C.(dec.).

Following similar procedures to those set forth above, the followingcompounds may also be prepared:

a. 4'-{2-[4-(p-fluorophenyl)-3,6-dihydrol(2l-l)pyridyl] ethoxypropionanilide hydrochloride, m.p. 244-246C. (from methanol-acetic acidethyl ester) from 4'-(2-bromoethoxy)-propionanilide and 4-(p-fluorophenyl )-l ,2,3 ,6-tetrahydropyridine;

b. 4'-{2-[4-(p-chlorophenyl)-3,6-dihydrol(2l-l)pyridyl] ethoxyisobutyranilide hydrochloride, m.p. 239246C. (from methanol-acetic acidethyl ester) from 4-(2-bromoethoxy)-isobutyranilide and 4-(p-chlorophenyl 1 ,2,3,6-tetrahydropyridine c. 4-{2-[4-(p-fluorophenyl)-3,6-dihydro- 1(2H)pyridyl]ethoxy}-isobutyranilide hydrochloride, m.p. 239241C. (frommethanol-acetic acid ethyl ester) from 4-(2-bromoethoxy)-isobutyranilideand 4- (p-fluorophenyl)-1,2,3 ,o-tetrahydropyridine;

d. 4'-{2-[4-(p-chlorophenyl)-3,6-dihydrol(2H)pyridyl] ethoxylacetanilidehydrochloride, m.p. 228229C. (from methanol-acetic acid ethyl ester)from 4-(2-bromoethoxy)-acetanilide and4-(pchloropheny1)-1,2,3,6-tetrahydropyridine;

e. 4'-{2-[4-(p-methoxyphenyl)-3,6-dihydro-1(2H)- pyridyl]ethoxy}acetanilide, m.p. l63164C. (from methanol) from4'-(2-bromoethoxy)acetanilide and4-(p-methoxyphenyl)-l,2,3,o-tetrahydropyridine.

The 4-(2-bromoethoxy)propionanilide employed as a starting material canbe manufactured as follows:

82.5 g. of p-propionamidophenol are introduced into a solution of 20 g.of sodium hydroxide in 20 ml. of water and 400 ml. of ethanol and, withstrong stirring, treated with 470 g. of 1,2-dibromoethane. The mixtureis heated under reflux conditions for 3 hours and the dibromoethane isdriven off with the aid of steam. The crude4-(2-bromoethoxy)propionanilide which precipitates is washed with waterand recrystallized from ethanol with the addition of water. The compoundmelts at 151C.

The 4-(2-bromoethoxy)isobutyranilide employed as starting material canbe manufactured in a manner analogous to that described above, mp. 143C.(from ethanol).

EXAMPLE 2 1.8 G. of 4'-[(2-chloroethyl)thio]acetanilide, 2.7 g. of4-(p-fluorophenyl)-1, 2, 3,6-tetrahydropyridine, 4.5 g. of potassiumcarbonate and a few crystals of potassium iodide are heated under refluxconditions in 50 ml. of ethanol and 5 ml. of water for 16 hours. Thesolvent is evaporated under reduced pressure, the residue is taken up inchloroform and washed with water. From the organic phase there isobtained crude 4'-{[2-[4-(pfluorophenyl)-3,6-dihydro-l(2H)-pyridyl]-ethyl]thio }acetanilide which melts at l50l52C. after recrystallizationfrom acetic acid ethyl ester.

The 4'-[(2-chloroethyl)thio]-acetanilide employed as starting materialcan be manufactured as follows:

A solution of 17.5 g. of 4'-[(2-hydroxyethyl)thio]- acetanilide in 500ml. of absolute benzene is treated dropwise with stirring with 17.5 g.of thionyl chloride and heated under reflux conditions for 1 hour. The

crude 4'-[(2-chloroethyl)thiol-acetanilide remaining behind afterevaporation of the solvent under reduced pressure melts at l53l55C.after repeated crystalli zation from acetic acid ethyl ester. A furthercrystallization can be obtained from the mother liquor by adsorption onsilica gel and elution with methylene chloride.

EXAMPLE 3 7.8 G. of4-{2-[4-(p-fluorophenyl)-3,6-dihydrol(2H)-pyridyl]-ethoxy}acetanilideand 40 ml. of about 20% hydrochloric acid are heated under refluxconditions for 1 hour. The crude p-{2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]ethoxy} aniline dihydrochloride hydrate whichprecipitates on cooling melts at l 83C. after recrystallization fromethanol-acetic acid ethyl ester-diethyl ether.

EXAMPLE 4 0.8 G. of p- {2-[4-(p-fluorophenyl)-3,6-dihydrol(2H)-pyridyl]ethoxy}aniline are dissolved in 10 ml. of 3-N acetic acid andtreated with 0.5 g. of acetic acid anhydride. The solution is stored atroom temperature for 12 hours and subsequently evaporated under reducedpressure. The residue is taken up in chloroform, this extract washedwith l-N caustic soda and evaporated. The residual crude4'-{2-[4-(p-fluorophenyl)- 3,6-dihydr9- 1 (2H )-pyridyl]ethoxy}acetanilide melts at 139C. after recrystallization from acetic acidethyl ester.

EXAMPLE 5 1 A solution of 4.5 g. of p-{2-[4-(p-fluorophenyl)-3,6-dihydro-l(2H)-pyridyl]ethoxy aniline in 15 ml. of chloroform is treatedwith 2 g. of triethylamine. A solution of 1.7 g. of methanesulfonic acidchloride in 10 m1. of chloroform is added thereto with stirring andcooling at a temperature range of O-lOC. The reaction mixture is allowedto stand at room temperature for 20 hours. It is washed with water andthe solvent is evaporated. The residual crude 4-{2[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-py idyl]ethoxy}- methanesulfonanilide melts at l37-l39C. after recrystallization from methanol.

EXAMPLE 6 0.1 G. of 4'-{2-[4-(p-fluorophenyl)-4- hydroxypiperidino]ethoxy}acetanilide are dissolved in 30 ml. of chloroform with slightheating and 0.2 g. of thionyl chloride are added. The mixture is heatedunder reflux conditions for 2 hours. The crude 4-{2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]- ethoxy acetanilidehydrochloride remaining after evaporation of the solvent melts at2l3-2l5C. (dec.) after recrystallization from methanol-diethyl ether.

The 4'-{2-[4-(p-fluorophenyl)-4-hydroxypiperidino]ethoxy}-acetanilideemployed as starting material can be manufactured as follows:

1.3 G. of 4-(p-fluorophenyl)-4-hydroxypiperidine, 1.85 g. of4-(2-bromoethoxy)-acetani1ide, l g. of potassium carbonate and a fewcrystals of potassium iodide are heated under reflux conditions in 20 mlof isopropanol for 24 hours. The residue remaining after evaporation ofthe solvent is taken up in chloroform and washed with water. The crude'4'-{2-[4-(pfluorophenyl)-4-hydroxypiperidind]- ethoxylacetanilideobtainable from the organic phase melts at 174-l75C. afterrecrystallization twice from isopropanol.

EXAMPLE 7 0.2 G. of 4- {2-[6-(p-fluorophenyl)-dihydro-6-methyl-Zl-l-l,3-oxazin-3-(4H)-yl]ethoxy}acetanilide hydrochloride and 2ml. of cone. hydrochloric acid are heated on the steam bath for 4 hours.The excess hydrochloric acid is evaporated under reduced pressure andthe residue brought to crystallization with ethanolacetic acid ethylester. The p-{2-[4-(p-fluorophenyl)-3,6-dihydro-l-(2l-l)-pyridyl]ethoxy} aniline dihyrdochloride hydrateobtained metls at l80-l83C. after recrystallization from ethanol-aceticacid ethyl ester.

The 4-{2-[6-(p-fluorophenyl)-dihydro-6lmethyl- ZH-l ,3-oxazin-3-(4H)-yl]-ethoxy} -acetanilide employed as starting material can bemanufactured as follows:

5.2 G. of 4'-(2-bromoethoxy)acetanilide, 4 g. of 6-methyl-6-(p-fluorophenyl)-tetrahydro-l ,3-oxazine, g.

- of potassium carbonate and a few crystals of potassium iodide areheated under reflux conditions in 50 ml. of ethanol for 16 hours. Afterevaporation of the solvent under reduced pressure, the residue isdissolved in chloroform and washed with water. The crude productobtained from the organic phase is adsorbed on silica gel and purifiedby elution with methylene chlorideether (1:1 There is obtained an oilwhich is converted into the hydrochloride as previously described. Thepure 4'-{2-[6-(p-fluorophenyl)-dihydro-6-methyl-2l-l-1,3-oxazin*3(4H)-yl]ethoxy} acetanilide melts at 180C. (dec.) afterrecrystallization from acetic acid ethyl ester.

EXAMPLE 8 A solution of 0.3 g. of l-[(p-aminophenoxy)acetyl]-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine in 5 ml. of absolutetetrahydrofuran is added dropwise at room temperature with stirring andnitrogen gassing to a suspension of 0.3 g. of lithium aluminum hydridein 10 ml. of absolute tetrahydrofuran. The stirring is continued at roomtemperature for 16 hours and water is cautiously added, initiallydropwise. After filtration, the mixture is extracted with chloroform.The oily residue is purified by column chromatography on silica gel withdiethyl ether-acetic acid ethyl ester (1:1) as eluting agent andconverted into the hydrochloride as previously described. Thep-{2-[4-(p-fluorophenyl)-3,6- dihydro-l(2l-l)-pyridyl]-ethoxy anilinedihydrochloride hydrate melts at 180183C. after crystallization withethanol-acetic acid ethyl ester-ether.

Thel-[(p-aminophenoxy)-acetyl]-4-(pfluorophenyl)-l,2,3,6-tetrahydropyridineemployed as starting material can be manufactured as follows:

A solution of 4.3 g. of p-nitrophenoxyacetic acid chloride in 10 ml. ofabsolute benzene is added dropwise with stirring and cooling to asolution of 3.6 g. of p-fluorophenyl-l,2,3,6-tetrahydropyridine and 5 g.of triethylamine in 20 ml. of absolute benzene and the reaction mixtureis heated under reflux conditions for 1 hour. After cooling, thetriethylamine hydrochloride thereby precipitated is extracted with waterand the organic phase is washed with 1N hydrochloric acid and water. Thecrude 4-(p-fluorophenyl)-l,2,3,6- tetrahydro-l-[(p-nitrophenoxy)acetyl]pyridine obtained after evaporation of the solvent melts atl34-l36C. after recrystallization from isopropanol.

2.3 g. of this compound and 2.5 g. of hydrazine hydrate are dissolved in50 ml. of absolute tetrahydrofuran. 0.2 g. of platinum dioxide are addedportionwise commencing the strong evolution of nitrogen. After cessationof the evolution of gas, the mixture is heated under reflux conditionsfor 15 hours and subsequently filtered. After evaporation of thesolvent, the residue is purified by column chromatography on silica gelwith methylene chloride as eluting agent. The 1-[(P' aminophenoxy)acetyl ]-4-(p-fluorophenyl)- l ,2,3 ,6- tetrahydropyridine obtained fromthe eluate melts at l20122C. 'after recrystallization from benzene.

EXAMPLE 9 0.3 g. of p-acetamidophenol are dissolved in a solution of0.12 g. of sodium in 10 ml. of absolute ethanol and 0.55 g. ofl-(2-chloroethyl)-4-(p-fluorophenyl)- 1,2,3,6-tetrahydropyridinehydrochloride are added thereto all at once. The reaction mixture isheated under reflux conditions for 24 hours, filtered from theprecipitated sodium chloride and the filtrate evaporated to dryness. Theresidue is adsorbed on silica gel and eluted with methylenechloride-ether (1:1). The 4'-{2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]-eth0xy}-acetanilide obtained from the eluate melts at 139C.after recrystallization from acetic acid ethyl ester.

The l-(2-chloroethyl)-4-(p-fluorophenyl)-l,2,3,6- tetrahydropyridineemployed as starting material can be manufactured as follows:

1.77 g. of 4-(p-fluorophenyl)-1,2,3,6- tetrahydropyridine, 0.8 g. ofethylene chlorohydrin, 1.2 g. of sodium carbonate and a few crystals ofsodium iodide are heated under reflux conditions in 10 ml. of ethanolfor 24 hours and filtered hot and the filtrate is evaporated to dryness.The residual oil is purified by column chromatography on silica gel withacetic acid ethyl ester-ethanol (1:1) as eluting agent. The l-(2-hydroxyethyl)-4-(p-fluorophenyl)-1,2,3 ,6- tetrahydropyridine obtainedfrom the eluate melts at 9698C. after recrystallization fromcyclohexane.

0.5 g. of 1-(2-hydroxyethyl)-4-(p-fluorophenyl)-l,2,3,-tetrahydropyridine are dissolved in 10 ml. of absolute benzeneand 0.5 g. of thionyl chloride are added with stirring and cooling withice. The mixture is heated under reflux conditions for 30 minutes andthe solvent is evaporated. The1-(2-chloroethyl)-4-(pfluorophenyl)-l,2,3,6-tetrahydropyridinehydrochloride obtained melts at 226C. after recrystallization fromethanol.

EXAMPLE 10 0.2 g. of powdered iron is added to a solution of 0.34 g. of4-(p-fluorophenyl)-l,2,3,6l-[2-(pnitrophenyoxy) ethyl]pyridine in amixture of 2 ml. of 1N hydrochloric acid, 10 ml. of ethanol and 10 ml.of water. The mixture is refluxed for 4 hrs., cooled and made alkalineby addition of 1N sodium hydroxide. After addition of 20 ml. ofchloroform and celite, the mixture is filtered. The organic phase isseparated, dried and evaporated. The oily residue obtained is dissolvedin ethyl acetate and converted to the hydrochloride by addition ofethanolic hydrogen chloride. Thel-[2-(p-aminophenoxy)ethyll-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine dihyrochloride obtained in this way has m.p.180-l 8 1 after recrystallization from ethanol/ethylacetate/ether.

EXAMPLE 1 1 Manufacture of capsules of the following composition:

hydrochloride 10 mg. Mannitol 110 mg. Talcum 5 mg. 125 mg.

The active substance is homogeneously mixed with the talcum andmannitol, passed through a No. 5 sieve (mesh width about 0.23 mm) andagain thoroughly mixed. The mixture obtained is filled into No. 4gelatin capsules.

EXAMPLE 12 Manufacture of dragees of the following composition:

hydrochloride 25 mg. Mannitol 100 mg. Corn starch mg. Talcum 5 mg.

The active substance is mixed with the mannitol and passed through a No.5 sieve (mesh width about 0.23 mm). A 10% aqueous paste is prepared fromthe corn starch and homogeneously mixed with the mannitolactivesubstance mixture. The slightly moist mash is passed through a No. 2sieve (mesh width about 1.0 mm). The granulate obtained is dried and,after the addition of the talcum, pressed to biconvex cores with aweight of mg. The cores are coated with a sugar layer in the usualmanner by dredging.

I claim:

1. A process for the preparation of a compound of wherein R signifieshydrogen, lower alkyl, lower alkanoyl, lower alkylsulfonyl, C to Ccycloalkyl or C to C cycloalkyl-lower alkyl; R signifies hydrogen, loweralkyl, C to C cycloalkyl or C to C cycloalkyl-lower alkyl; R signifiesfluorine, chlorine or lower alkoxy; X signifies an oxygen atom or asulfur atom consisting essentially of reacting a compound of the formulawherein R R R and X are as described above with a mineral acid at atemperature of about 0C to reflux temperature for a prolonged period oftime.

1. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA